Dysregulation of Akt-FOXO1 Pathway Leads to Dysfunction of Regulatory T Cells in Patients with Psoriasis.

Psoriasis is a T lymphocyte-driven systemic inflammatory disease. Regulatory T cells (Tregs) are essential for establishing and maintaining immune tolerance. In this study, we found that patients with psoriasis and healthy controls had comparable percentages of circulating CD4CD25FOXP3 Tregs, but psoriatic Tregs had reduced suppressive function. Thereafter, mRNA arrays were performed to study the gene expression profile of psoriatic Tregs. Psoriatic Tregs expressed high levels of a T helper type 1-like transcription factor and cytokines such as T-bet and IFN-γ. Furthermore, we found that FOXO1 can bind to the promoter of TBX21 to inhibit its expression, thus keeping the suppressive function of Tregs. However, an increase in protein kinase B-mediated phosphorylation of FOXO1 was observed in psoriatic Tregs, which subsequently caused FOXO1 inactivation by nuclear exclusion. In addition, incubation of healthy Tregs with psoriatic serum led to the activation of protein kinase B, nuclear exclusion of FOXO1, and the loss of FOXO1 transcription activity. The role of FOXO1 in regulating the function of Tregs was corroborated using a psoriasis-like mouse model in which Foxo1-deficient Tregs failed to protect mice from developing psoriasis. In conclusion, our findings reveal that the dysregulation of the protein kinase B-FOXO1 pathway may be a critical cause of Treg dysfunction in psoriasis.